15-32101283-CTTTTTTT-CTTTTTTTTTT

Variant names:

• chr15-32101283-C-CTTT
• rs34476605
• NM_000746.6:c.196-7_196-5dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000746.6(CHRNA7):​c.196-7_196-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,443,132 control chromosomes in the GnomAD database, including 70 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (45 hom., cov: 0)
  • Exomes 𝑓: 0.018 (25 hom.)
• Consequence: CHRNA7 NM_000746.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.508
• Publications: 1 publications found

Genes affected

CHRNA7 (HGNC:1960): (cholinergic receptor nicotinic alpha 7 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA7 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• epilepsy

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0191 (2703/141312) while in subpopulation AFR AF = 0.036 (1379/38350). AF 95% confidence interval is 0.0344. There are 45 homozygotes in GnomAd4. There are 1271 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2703 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000746.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	NM_000746.6	MANE Select	c.196-7_196-5dupTTT		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-7_283-5dupTTT		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-7_308-5dupTTT		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.196-7_196-5dupTTT		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-7_61-5dupTTT		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-7_196-5dupTTT		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2702 AN: 141310 Hom.: 45 Cov.: 0

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00574

Gnomad SAS AF: 0.00359

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0191 AC: 2819 AN: 147816 AF XY: 0.0188

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0184 AC: 23905 AN: 1301820 Hom.: 25 Cov.: 26 AF XY: 0.0180 AC XY: 11662 AN XY: 648766

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0252 AC: 713 AN: 28260

American (AMR) AF: 0.0180 AC: 526 AN: 29220

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 232 AN: 22666

East Asian (EAS) AF: 0.0153 AC: 559 AN: 36438

South Asian (SAS) AF: 0.0152 AC: 1092 AN: 71828

European-Finnish (FIN) AF: 0.0118 AC: 559 AN: 47226

Middle Eastern (MID) AF: 0.00856 AC: 43 AN: 5024

European-Non Finnish (NFE) AF: 0.0191 AC: 19275 AN: 1007210

Other (OTH) AF: 0.0168 AC: 906 AN: 53948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0191 AC: 2703 AN: 141312 Hom.: 45 Cov.: 0 AF XY: 0.0187 AC XY: 1271 AN XY: 68042

African (AFR) AF: 0.0360 AC: 1379 AN: 38350

American (AMR) AF: 0.0109 AC: 155 AN: 14234

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 5 AN: 3396

East Asian (EAS) AF: 0.00577 AC: 28 AN: 4856

South Asian (SAS) AF: 0.00339 AC: 15 AN: 4424

European-Finnish (FIN) AF: 0.00340 AC: 25 AN: 7362

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.0163 AC: 1070 AN: 65568

Other (OTH) AF: 0.0123 AC: 24 AN: 1946

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34476605; hg19: chr15-32393486;